Aggregation-induced integrated stress response rejuvenates culture-expanded human mesenchymal stem cells.
Aggregation-induced integrated stress response rejuvenates culture-expanded human mesenchymal stem cells.
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DOI：
10.1002/bit.27474
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发表时间：
2020-10
影响因子：
3.8
通讯作者：
Ma T
中科院分区：
文献类型：
--
作者：
Bijonowski BM;Fu Q;Yuan X;Irianto J;Li Y;Grant SC;Ma T
蛋白质稳态对细胞功能至关重要，因为稳态的丧失归因于衰老和不需要的蛋白质的积累。人类间充质干细胞（MSC）由于其分泌炎症调节剂、血管生成和再生细胞因子的能力而显示出有希望的治疗潜力。然而，存在具有受损治疗质量的人MSC扩增的问题。在体外扩增过程中，将人MSC接种在硬塑料上并进行培养适应，这导致异常增殖、代谢改变和自噬活性降低。以前已经表明，三维（3D）聚集可以通过提高自噬和恢复代谢状态回到幼稚表型来逆转其中一些改变。为了进一步了解人MSC培养物中的蛋白质稳态，本研究调查了3D聚集对人MSC蛋白质组的影响，以确定聚集改变的特定途径。将来源于骨髓（bMSC）和脂肪组织（ASC）的人MSC的3D聚集体和2D培养物与分化的人真皮成纤维细胞（FB）一起沿着分析。蛋白质组学分析表明，真核生物起始因子2途径的升高和三维聚集体中整合应激反应（ISR）活性的上调。特异性蛋白定量进一步确定了bMSC和ASC对ISR有反应，而FB没有。3D聚集显著增加了bMSCs和ASCs的缺血存活。用小分子salubrinal和GSK2606414干扰ISR导致bMSC、ASC和FB的不同反应。这项研究表明，基于聚集的预处理培养具有通过建立ISR和稳态来提高扩增的人MSC的治疗功效的潜力。
Protein homeostasis is critical for cellular function, as loss of homeostasis is attributed to aging and the accumulation of unwanted proteins. Human mesenchymal stem cells (MSCs) have shown promising therapeutic potential due to their impressive abilities to secrete inflammatory modulators, angiogenic, and regenerative cytokines. However, there exists the problem of human MSC expansion with compromised therapeutic quality. Duringin vitro expansion, human MSCs are plated on stiff plastics and undergo culture adaptation, which results in aberrant proliferation, shifts in metabolism, and decreased autophagic activity. It has previously been shown that three-dimensional (3D) aggregation can reverse some of these alterations by heightening autophagy and recovering the metabolic state back to a naïve phenotype. To further understand the proteostasis in human MSC culture, this study investigated the effects of 3D aggregation on the human MSC proteome to determine the specific pathways altered by aggregation. The 3D aggregates and 2D cultures of human MSCs derived from bone marrow (bMSC) and adipose tissue (ASC) were analyzed along with differentiated human dermal fibroblasts (FB). The proteomics analysis showed the elevated eukaryotic initiation factor 2 pathway and the upregulated activity of the integrated stress response (ISR) in 3D aggregates. Specific protein quantification further determined that bMSC and ASC responded to ISR, while FB did not. 3D aggregation significantly increased the ischemic survival of bMSCs and ASCs. Perturbation of ISR with small molecules salubrinal and GSK2606414 resulted in differential responses of bMSC, ASC, and FB. This study indicates that aggregation-based preconditioning culture holds the potential for improving the therapeutic efficacy of expanded human MSCs via the establishment of ISR and homeostasis.
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影响因子：
--
作者：
Chen KH;Chen CH;Wallace CG;Yuen CM;Kao GS;Chen YL;Shao PL;Chen YL;Chai HT;Lin KC;Liu CF;Chang HW;Lee MS;Yip HK
通讯作者：
Yip HK
影响因子：
16
作者：
Kroemer G;Mariño G;Levine B
通讯作者：
Levine B
影响因子：
4.3
作者：
Bejoy, Julie;Yuan, Xuegang;Li, Yan
通讯作者：
Li, Yan
DOI：
10.1002/stem.2587
发表时间：
2017-05
期刊：
Stem cells (Dayton, Ohio)
影响因子：
--
作者：
Diaz MF;Vaidya AB;Evans SM;Lee HJ;Aertker BM;Alexander AJ;Price KM;Ozuna JA;Liao GP;Aroom KR;Xue H;Gu L;Omichi R;Bedi S;Olson SD;Cox CS Jr;Wenzel PL
通讯作者：
Wenzel PL
影响因子：
12.4
作者：
Hashem Y;Frank J
通讯作者：
Frank J